Immunotherapy With Nivolumab and Ipilimumab Followed by Nivolumab or Nivolumab With Cabozantinib for Patients With Advanced Kidney Cancer, The PDIGREE Study
N
Nabil Adra, MD
Primary Investigator
Overview
This phase III trial compares the usual treatment (treatment with ipilimumab and nivolumabwed by nivolumab alone) to treatment with ipilimumab and nivolumab, followed byvolumab with cabozantinib in patients with untreated renal cell carcinoma that has spreadher parts of the body. The addition of cabozantinib to the usual treatment may make it
work better. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may
help the body's immune system attack the cancer, and may interfere with the ability of tumorgrow and spread. Cabozantinib may stop the growth of tumor cells by blocking some ofhe enzymes needed for cell growth. It is not yet known how well the combination ofbozantinib and nivolumab after initial treatment with ipilimumab and nivolumab works ing patients with renal cell cancer that has spread to other parts of the body.
Description
PRIMARY OBJECTIVE:
I. To compare the overall survival (OS) in patients with metastatic renal cell cancer (RCC)d with ipilimumab-nivolumab followed by either nivolumab versus cabozantinib-nivolumab.
SECONDARY OBJECTIVES:
I. To determine progression free survival (PFS) of patients treated with nivolumab versusvolumab-cabozantinib.
II. To evaluate the 12-month complete response rate in patients treated withumab-nivolumab followed by cabozantinib-nivolumab versus ipilimumab-nivolumab followed
by nivolumab (patients who have complete response [CR] and relapse before 12 months will not
be counted as a CR at 12-months).
III. To evaluate the rates of discontinuing therapy at 1 year. IV. To compare objective(ORR, assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1d Immune Response Evaluation Criteria in Solid Tumors [iRECIST] criteria) for patientsd with ipilimumab-nivolumab followed by cabozantinib-nivolumab versusumab-nivolumab followed by nivolumab.
V. To document the adverse event profile of ipilimumab-nivolumab followed bybozantinib-nivolumab.
BIOMARKER OBJECTIVES:
I. To evaluate biomarkers associated with exceptional responses in both arms (exceptionaldefined as CRs with treatment discontinuation at 12 months or 24 months).
II. To evaluate whether baseline IL-6 is predictive of outcome in patients treated withbozantinib-containing regimen.
QUALITY OF LIFE (QOL) OBJECTIVES:
I. To compare health-related quality of life at 18 months post-registration as assessed byhe Functional Assessment of Cancer Therapy (FACT)-Kidney Symptom Index 19 (FKSI-19) betweendomized to nivolumab (nivo) versus (vs) cabozantinib (cabo)/nivo.
II. To compare health-related quality of life as assessed by the FKSI-19 between patientsdomized to nivo vs cabo/nivo at other time points.
III. To compare patient-reported fatigue using Patient-Reported Outcomes Measurementystem (PROMIS)-Fatigue between patients randomized to nivo vs cabo/nivo.
IV. To compare quality-adjusted survival (overall survival x utility score assessed byuroQol five-dimensional questionnaire [EQ5D-5L]) between patients randomized to nivo vsbo/nivo.
TLINE
INDUCTION: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IVver 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absencedisease progression or unacceptable toxicity.
TREATMENT
Patients with unconfirmed but clinical progression of disease (iuPD) with clinicalbility receive cabozantinib orally (PO) daily on days 1-28. Treatment repeats every 28
days until further disease progression or unacceptable toxicity.
Patients with unconfirmed CR (iCR) receive nivolumab IV between 30-60 minutes on day 1.
Treatment repeats every 28 days in the absence of disease progression or unacceptabley.
Patients with non-CR/non-PD or iuPD with clinical stability are randomized to 1 of 2 arms.
ARM A: Patients receive nivolumab IV between 30-60 minutes on day 1. Treatment repeats every
28 days in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive nivolumab IV between 30-60 minutes on day 1 and cabozantinib PO dailydays 1-28. Treatment repeats every 28 days in the absence of disease progression or
unacceptable toxicity.
Patients undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) and bloodhroughout the study.
Eligibility
You may be eligible for this study if you meet the following criteria:
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Conditions:
Clear Cell Renal Cell Carcinoma, Metastatic Malignant Neoplasm in the Bone, Metastatic Malignant Neoplasm in the Lymph Nodes, Metastatic Malignant Neoplasm in the Soft Tissues, Metastatic Malignant Neoplasm in the Viscera, Sarcomatoid Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8, Stage IV Renal Cell Cancer AJCC v8
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Age: 18 Years
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Gender: All
Inclusion Criteria:
- STEP I REGISTRATION CRITERIA
- Histologically documented renal cell carcinoma with clear cell component, includingwho have sarcomatoid or rhabdoid features
- Any metastatic disease, including visceral, lymph node, other soft tissue and bone,urable per RECIST 1.1.
- Measurable disease as defined in the protocol.
- Must be intermediate or poor risk patient per International Metastatic Renal CellCarcinoma Database (IMDC) criteria (1 or more of the following): Karnofsky performanceus [KPS] < 80, < 1 year from diagnosis [including initial nephrectomy] to systemicdisease, hemoglobin less than lower limit of normal [LLN],d calcium concentration greater than upper limit of normal [ULN], absoluteutrophil count greater than ULN, platelet count > ULN).
- Central nervous system (CNS) disease permitted, if stable and not otherwise causingymptoms or needing active treatment.
- Karnofsky performance status >= 70%.
- No prior treatment with PD-1, PD-L1, or CTLA-4 targeting agents (including but notd to nivolumab, pembrolizumab, pidilizumab, durvalumab, atezolizumab,umab, and ipilimumab), or any other drug or antibody specifically targetingT-cell co-stimulation or checkpoint pathways. The only exception is for priorwith nivolumab or other PD-1/PD-L1/CTLA-4 targeting therapy on pre- orve trials, as long as > 1 year since completion of systemic therapy.
- No prior previous systemic therapy for renal cell carcinoma (prior HD IL-2 [> 28 days]d prior adjuvant sunitinib > 180 days since completion and prior immunotherapy asbove are allowed).
- No systemic cancer therapy less than 28 days prior to registration; no radiationherapy less than 14 days prior to registration. There must be a complete recovery andgoing complications from radiotherapy.
- Not pregnant and not nursing, because this study involves an agent that has knowngenotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearingy, a negative serum or urine pregnancy test done =< 14 days prior togistration is required.
- Age >= 18 years
- Absolute neutrophil count (ANC) >= 1,500/mm^3.
- Platelet count >= 100,000/mm^3.
- Hemoglobin >= 8 g/dL.
- Calculated (Calc.) creatinine clearance >= 30 mL/min.
- Urine protein =< 1+ or urine protein to creatinine (UPC) ratio < 1.
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (except for patients with knownkely Gilbert's syndrome, for whom total bilirubin up to 3 mg/dL is allowed withdirect bilirubin =< 20% total bilirubin)
- Aspartate aminotransferase/alanine aminotransferase (AST/ALT) =< 2.5 x upper limit of(ULN) or < 5 x ULN if hepatic metastases present.
- STEP 2 REGISTRATION ELIGIBILITY CRITERIA
- Successful completion of at least 1 cycle of ipilimumab/nivolumab.
- Resolution of any treatment-related adverse events to grade 1 or less per dosedification section (this criteria does not include any adverse events [AEs] notbutable to treatment which are present due to disease), withdnisone-equivalent dosing at 10 mg daily or less. Exceptions for this criteriaude patients receiving replacement hormone treatments (such as levothyroxine ford hypothyroidism or glucocorticoid replacement for adrenalufficiency). Please contact study chair if further discussion is needed.
- No more than 80 days from last dose of ipilimumab/nivolumab.
Exclusion Criteria:
- Active autoimmune disease requiring ongoing therapy.
- Ongoing acute toxicity > grade 2 from previous treatment.
- History of severe allergic, anaphylactic or other hypersensitivity reactions tohimeric or humanized antibodies.
- Active hepatitis B/C, or active tuberculosis (PPD response without active TB iswed)
- Human immunodeficiency virus (HIV) -infected patients with detectable viral loadwithin 6 months prior to registration. Patients on effective anti-retroviral therapywith undetectable viral load within 6 months prior to registration are eligible.
- Concurrent use of immunosuppressive medication including prednisone above 10 mg daily.
- Uncontrolled adrenal insufficiency.
- Uncontrolled hypertension (systolic blood pressure [BP] >150 mmHg or diastolic BP > 90Hg).
- Major surgery less than 28 days prior to registration.
- Any serious non-healing wound, ulcer, or bone fracture within 28 days prior togistration.
- Any arterial thrombotic events within 180 days prior to registration.
- Clinically significant hematuria, hematemesis, or hemoptysis within 12 weeks prior togistration.
- Cavitating pulmonary lesions or known endotracheal or endobronchial disease.
- Lesions encasing or invading any major blood vessels (this does not include tumorhrombus extending into/through renal vein/inferior vena cava [IVC]). Patients withumor thrombus extending into/through renal vein are considered eligible.
- Moderate of severe hepatic impairment (Child-Pugh B or C).
- Any history of untreated pulmonary embolism or deep venous thrombosis (DVT) in the 180days prior to registration. (Any asymptomatic, treated pulmonary embolism orymptomatic, treated deep venous thrombosis > 30 days prior to registration allowed).
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms.
- Unstable cardiac arrhythmia within 6 months prior to registration.
- Any gastrointestinal (GI) bleeding =< 180 days, hemoptysis, or other signs ofulmonary hemorrhage =< 90 days prior to registration.
- History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess,bowel obstruction, or gastric outlet obstruction within 180 days prior togistration.
- Active peptic ulcer disease, inflammatory bowel disease, or malabsorption syndromewithin 28 days prior to registration.
- Untreated hypothyroidism (treated hypothyroidism on thyroid replacement therapy iswed. Abnormal thyroid-stimulating hormone (TSH) is acceptable with normal T3/freeT4 if treated on thyroid replacement therapy)
- Evidence of pancreatitis, history of organ transplant, or history of congenital QTyndrome.
- Active treatment with coumarin agents (e.g., warfarin), direct thrombin inhibitors(e.g., dabigatran), direct Xa inhibitor betrixaban or platelet inhibitors (e.g.,dogrel) within 5 days of registration. Allowed anticoagulants include:hylactic use of low-dose aspirin for cardio-protection (per local applicableguidelines) and low-dose low molecular weight heparins (LMWH), therapeutic doses ofLMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban,ban. Allowed also in patients with known brain metastases who are on a stabledose of the anticoagulant for at least 1 week prior to registration without clinicallygnificant hemorrhagic complications from the anticoagulation regimen or the tumor.
- Significant cardiac ischemia events (ST elevation myocardial infarction [STEMI] orT elevation myocardial infarction [NSTEMI]) within 6 months or active NY HeartAssociation class 3-4 heart failure symptoms
Updated on
05 May 2024.
Study ID: NCI-2018-03694
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